# Restructuring Antiviral Quinazolinone Frameworks to Derive and Optimize Inhibitors of Chikungunya Virus

## TL;DR

Researchers optimized a quinazolinone compound to effectively inhibit Chikungunya virus in human cells, showing promise for future antiviral development.

## Contribution

The study reengineered antiviral quinazolinones to achieve potent inhibition of Chikungunya virus with improved cellular activity.

## Key findings

- (R)-1h (BDGR-651) reduced CHIKV titer by 4.1 log at 10 μM in human dermal fibroblasts.
- Compound (R)-1h showed excellent solubility and stability in mouse microsomes and plasma.
- Confocal microscopy confirmed a dose-dependent protective effect of (R)-1h in infected Vero E6 cells.

## Abstract

Chikungunya virus (CHIKV) results in debilitating chronic
pain
in nearly half of those infected. With no FDA approved small molecule-based
therapeutics available, we screened compounds to reveal quinazolinone
(S)-1a with a modest 0.3 log reduction
of CHIKV titer and no significant toxicity (CC50 > 40
μM).
Five scaffold regions were surveyed to improve the titer reduction
efficiency. Chemistry was established to preserve the enantiopurity
of 2-piperidinyl-containing analogues, affording (R)-1h (BDGR-651) which reduced CHIKV titer in normal
human dermal fibroblasts by 4.1 log at 10 μM (EC50 = 0.86 μM). Excellent solubility and mouse microsomal and
plasma stabilities were observed, and confocal microscopy of infected
Vero E6 cells treated with (R)-1h showed
a dose-dependent protective effect. A narrow selectivity index prevented in vivo evaluation, but the study showed that antiencephalitic
alphavirus quinazolinones could be reengineered to inhibit CHIKV,
an arthritogenic virus, against which previous analogues showed no
significant activity.